Sciencemadness Discussion Board - Sober Etaoin Shrdlu Challenge #1 - OTC TEMPO

As I said in the other thread, I will attempt this.

I eagerly await your results. Seems like a ten day minimim experiment. If you want to PM about it at some point, let me know. You posted on it first, so I am not trying to scoop your ideas or work.

blogfast25 - 15-11-2014 at 05:35

Quote: Originally posted by Etaoin Shrdlu

2. You can skip steps to non-OTC intermediates if you can link to a confirmed synthesis already performed and written up on ScienceMadness. Patent/research paper writeups must be confirmed by yourself or someone on ScienceMadness no matter how awesome they are.

To be clear, the SM post I linked to has at least three people synthing 2,2,6,6 tetramethylpiperidin-4-one. Does Rule 2. mean a challenger could use bought 2,2,6,6 tetramethylpiperidin-4-one? It would save time, of course.

Second question: would H3PO4 be considered OTC? In my country I can get it easily: eBay and also other sites.

EditI don't care about winning, but I don't see why one couldn't try something such as:
1. acetone self condensation to phorone
2. phorone animation with ammonia (can be one pot with above under right conditions).

No need for phorone: read the thread you linked too; acetone + NH3 works just fine (several variants) for 2,2,6,6 tetramethylpiperidin-4-one.

[Edited on 15-11-2014 by blogfast25]

Etaoin Shrdlu - 15-11-2014 at 05:48

Yes, if they confirmed they really had usable 2,2,6,6 tetramethylpiperidin-4-one. (I think they did.) You'd still have to provide a clear writeup of how to get there, though.

Second question: would H3PO4 be considered OTC? In my country I can get it easily: eBay and also other sites.

Yes. It is used as masonry cleaner and rust remover among other things in fairly high concentrations. I believe there is an OTC synth somewhere on this site as well.

[Edited on 11-15-2014 by Etaoin Shrdlu]

blogfast25 - 15-11-2014 at 06:03

Thanks, ES.

Chemosynthesis - 15-11-2014 at 06:12

Second question: would H3PO4 be considered OTC? In my country I can get it easily: eBay and also other sites.

No need for phorone: read the thread you linked too; acetone + NH3 works just fine (several variants) for 2,2,6,6 tetramethylpiperidin-4-one.

1. While judging, remember it's in Coca Cola, though that hardly seems as viable volumetric/molarity-wise compared to hydroponics or the like.
2. Yeah, I hadn't tracked down J. Am. Chem. Soc., 79:5447 (1957) yet at that point or finished the thread to confirm 100% before editing. I guess that dramatically reduces time to completion.

blogfast25 - 15-11-2014 at 06:34

2,2,6,6 tetramethylpiperidin-4-one (aka triacetonamine) from Sigma:

http://www.sigmaaldrich.com/catalog/product/aldrich/459119?l...

As usual a bit pricy from the people with a 'licence to print money' but still.

Amos - 15-11-2014 at 06:55

Phosphoric acid is definitely OTC; I can buy a gallon jug of 40% H3PO4 at Home Depot as Klean-Strip Prep & Etch.

DrMario - 15-11-2014 at 08:19

You can get 75% phosphoric acid sold as "anti-rust" solution.

Metacelsus - 15-11-2014 at 17:47

2,2,6,6 tetramethylpiperidin-4-one (aka triacetonamine) from Sigma:

http://www.sigmaaldrich.com/catalog/product/aldrich/459119?l...

As usual a bit pricy from the people with a 'licence to print money' but still.

The prize is $300, and the 100 g bottle "only" costs $75 (even with shipping, still not as much as $300). Still, buying from Sigma is against the spirit of the challenge.

By the way, have a look at my start (gassing acetone/methanol/ammonium chloride with ammonia):

Photo on 11-15-14 at 3.10 PM.jpg - 187kB

After keeping the mixture at 50 C for 3 hours, it's turned a light orange. I'll let it react overnight.

[Edited on 16-11-2014 by Cheddite Cheese]

blogfast25 - 16-11-2014 at 05:00

Still, buying from Sigma is against the spirit of the challenge.

The ‘spirit’, LOL? I’m a material boy.

See his response to my question, here:

Quote: Originally posted by Etaoin Shrdlu

Yes, if they confirmed they really had usable 2,2,6,6 tetramethylpiperidin-4-one. (I think they did.) You'd still have to provide a clear writeup of how to get there, though.

Chemosynthesis - 17-11-2014 at 02:53

I am particularly curious to see if the expected TEMPO can be used for OTC acetonitrile:
DOI: 10.1055/s-0033-1338489

CuReUS - 18-11-2014 at 05:42

i was completely disheartened after seeing that TEMPO could be made so easily from acetone and ammonia .
my method used malonyl choride (malonic acid can be made by oxidising malic acid ,which is OTC sold at home brew supplies ,with sodium hypochlorite)
see the 7th post by boffis in this thread for malonic acid-http://www.sciencemadness.org/talk/viewthread.php?tid=1600&a...

then malonic acid is converted to malonyl chloride using SOCl₂ (thionyl choride can be extracted from batteries)
http://en.wikipedia.org/wiki/Thionyl_chloride#Batteries

then di-isopropylamine oxide is made (di isopropyl amine is made using isopropyl bromide and saccharin and then oxidized using hydrogen peroxide)

see this -use of saccharin as an alternative to pthalimide
http://pubs.acs.org/doi/abs/10.1021/ar00010a001?journalCode=...

and this thread ,8th post by chordate http://www.sciencemadness.org/talk/viewthread.php?tid=11081&...

finally malonyl choride and di-isopropylamine oxide is reacted in the presence of strong base (NaNH₂ ) to form TEMPO 3,5 diketone

it is then reduced using hydrazine to get TEMPO

Quote:

I am particularly curious to see if the expected TEMPO can be used for OTC acetonitrile:
DOI: 10.1055/s-0033-1338489

chemosynthesis ,acetonitrile can be made easily from ethylamine using 30% hydrogen peroxide and conc sulphuric acid

ethylamine can be made using ethylbromide and hexamine (delepine reaction)
http://en.wikipedia.org/wiki/Del%C3%A9pine_reaction

take ethylamine and conc H₂SO₄ in a beaker
then slowly drip in 30% H₂O₂ into the beaker .
what happens is that the peroxide oxidises ethylamine to N-ethyl hydroxyl amine and the sulphuric acid immediately dehydrates the hydroxyl amine to give acetonitrile

since the hydroxyl amine is very prone to furthur oxidation by peroxide to form nitroethane ,the concentration of peroxide is kept at a minimum and any hydroxyl amine formed is immediately dehydrated as there is an excess of H₂SO₄ .
gentle heating of the beaker containing the (amine +acid) is required throughout the reaction

but obviously the one pot synthesis using TEMPO at room temp is much easier
and tert -butyl hypochlorite can be easily made
http://www.orgsyn.org/demo.aspx?prep=cv5p0184

Chemosynthesis - 18-11-2014 at 06:48

Thanks. Delepine is a good fit for this small amine, though Gabriel synthesis is technically OTC as well, as is the modification using saccharine as a substitute, which you've obviously used to good effect with an additional alkylation during unmasking.

Quote:

take ethylamine and conc H₂SO₄ in a beaker
then slowly drip in 30% H₂O₂ into the beaker .
what happens is that the peroxide oxidises ethylamine to N-ethyl hydroxyl amine and the sulphuric acid immediately dehydrates the hydroxyl amine to give acetonitrile

since the hydroxyl amine is very prone to furthur oxidation by peroxide to form nitroethane ,the concentration of peroxide is kept at a minimum and any hydroxyl amine formed is immediately dehydrated as there is an excess of H₂SO₄ .
gentle heating of the beaker containing the (amine +acid) is required throughout the reaction

but obviously the one pot synthesis using TEMPO at room temp is much easier

Interesting. What are yields like? The only lit I saw on this used expensive ruthenium catalysis.
DOI: 10.1039/C3GC36513A

CuReUS - 18-11-2014 at 09:00

chemosynthesis ,i am very sorry

you can dehydrate aldoximes to nitriles ,not hydroxyl amines
but nitriles can still be made from OTC chemicals

ethylamine could be oxidised to acetaldehyde(as acetaldehyde is not OTC),read the acetaldehyde synthesis in the organic chemistry section for more ways to make it
http://en.wikipedia.org/wiki/Ethylamine#Reactions_and_applic...

hydroxylamine could be prepared from nitromethane or just brought as HCl salt

http://www.sciencemadness.org/talk/viewthread.php?tid=15176

acetaldehyde oxime could be prepared and dehydrated to give nitriles

alternatively ,oximes could be prepared from reactions with nitrites(which can be found OTC in deodorants)
http://en.wikipedia.org/wiki/Oxime#Preparation

you could also make nitriles by oxidizing amines using TCCA
http://www.organic-chemistry.org/synthesis/C3N/nitriles.shtm

actually i am very depressed as i thought for two days to get a decent route for making TEMPO and then i see this method from acetone and ammonia

its like microwave cooking Vs bonfire

formaldehyde + ammmonia -hexamine
acetone +ammonia-TEMP
then acetaldehyde +ammonia=???

nicodem would to kill me if he/she saw my post

Chemosynthesis - 18-11-2014 at 10:26

Thanks. I would probably use nitrites from butcher's salts or pickling (preservative) due to relative purity rather than deodorants.

I am particularly interested in a TEMPO route, though, and it appears to be able to improve upon TCCA oxidation in many instances (Synthesis, 2003, 2629-2631).

Etaoin Shrdlu - 18-11-2014 at 10:59

actually i am very depressed as i thought for two days to get a decent route for making TEMPO and then i see this method from acetone and ammonia

Don't be depressed. I'm excited someone thought up a different path than acetone condensation.

aga - 19-11-2014 at 12:27

Depressed ?!?!

I would be ECSTATIC if i worked out a functioning route to TEMPO.

The fact that you worked it out is proof positive that you are at a level of understanding that many of us can only dream of.

The fact that Other routes exist would do absolutely nothing to dampen my happiness, and neither should it dampen yours.

Nicodem - 19-11-2014 at 13:08

Quote: Originally posted by aga

The fact that you worked it out is proof positive that you are at a level of understanding that many of us can only dream of.

I think he was referring to his pipe dream synthesis. Even though he calls it "my method" as if it was some proven synthesis, it is quite obviously a fabrication, as it makes no sense:

then di-isopropylamine oxide is made (di isopropyl amine is made using isopropyl bromide and saccharin and then oxidized using hydrogen peroxide)

...

finally malonyl choride and di-isopropylamine oxide is reacted in the presence of strong base (NaNH₂ ) to form TEMPO 3,5 diketone

it is then reduced using hydrazine to get TEMPO

I would feel equally depressed, if I came up with such ideas.

aga - 19-11-2014 at 13:10

Doh.

Etaoin Shrdlu - 19-11-2014 at 17:11

Quote: Originally posted by Nicodem

finally malonyl choride and di-isopropylamine oxide is reacted in the presence of strong base (NaNH₂ ) to form TEMPO 3,5 diketone

I would feel equally depressed, if I came up with such ideas.

I thought I saw where he was going with this when I glanced over it earlier but looking at it again I'd expect just a bunch of malonamide. Still, would appreciate to know what makes it particularly depressing, and would be interested what the actual thought process behind it was.

Metacelsus - 19-11-2014 at 18:32

Yeah, sodium amide probably wouldn't work; you'd need a non-nucleophilic base.

By the way, I'm almost done on my batch of triacetonamine. I should have the workup done by the end of the weekend.

[Edited on 20-11-2014 by Cheddite Cheese]

CuReUS - 20-11-2014 at 09:30

Yeah, sodium amide probably wouldn't work; you'd need a non-nucleophilic base.

it is a non nucleophilic base,when it is used in the "absence" of ammonia or other polar liquids that are electron rich

http://www.masterorganicchemistry.com/2011/07/29/reagent-fri...

read the last heading on that page -"conversion of acyl halides to amides

and this
http://en.wikipedia.org/wiki/Sodium_amide#Uses

actually in all the reactions i saw in which soda amide was used to alkylate ,carboxylic acids or esters were used .
even if the base pulled out a hydrogen from the COOH ,it would go into resonance and not interfere in the reaction at all
and for esters,there is no hydrogen itself ,so there is no problem .
that made me wrongly assume that the same thing would happen for acid chloride
but i came up with another method
instead of malonyl chloride ,we can use 1,3 dichloropropane
which can be made from propan 1,3 diol
http://en.wikipedia.org/wiki/1,3-Propanediol
the wiki page says that it is used in antifreeze
it can be also made by hydration of acrolein,which in turn can be made by dehydration of glycerol or by just heating glycerol
http://en.wikipedia.org/wiki/Acrolein#Production

although i couldnt find an article for making 1,3 dichloropropane ,i saw this
http://www.orgsyn.org/demo.aspx?prep=cv6p0556
under "discussion"
"in one instance, 1,3-dibromopropane was treated with sodium thiosulfate to form a precursor of the dithiol ...."
so similarly could the diol be refluxed with HCl in the presence of anhydrous ZnCl₂ or treated with thionyl choride to get the dichoro
then disopropylamine oxide is treated with sodamide or tertbutoxide ,aluminum isopropoxide ,sodium ethoxide or just plain old alcoholic KOH to deprotonate it
this is treated with the 1,3 dichloro to get TEMPO

(instead of doing it in one pot,one could first react the di-iso oxide with the base to deprotonate it,then drip that slowly into a flask of 1,3 dichloro propane .since there will be very less unreacted amide in every drop and there is an excess of the dichloro,such substitution side reactions could be avoided.most of the ammonia formed in the first reaction would bubble out and even if some came into the flask and caused some dichloro molecules to be substituted,HCl would form that would neutralize the remaining ammonia)

instead of substitution ,some of the dichloro may get dehydrohalogenated.but cant alkenes also act as nucleophiles
http://www2.dupont.com/Sustainable_Solutions/en_US/assets/do...
and since only very little unreacted sodamide from the first beaker will cause this dehydrohalogenation,i dont think both the chlorine atoms will be removed
so in the worst case scenario ,allyl chloride will form which can still carry out the reaction

i didnt know that propan 1,3 diol was OTC ,or i would have never used malonyl chloride
my first idea was to use this

http://en.wikipedia.org/wiki/Bis%28chloromethyl%29_ketone

[Edited on 21-11-2014 by CuReUS]

Praxichys - 21-11-2014 at 16:35

Hey Cheddite, how did the workup go? Any luck? I'm on my way with the gassing...

Metacelsus - 21-11-2014 at 16:57

I'm still doing it. I said it would be done by the end of the weekend, and I still think it will be.

CuReUS - 22-11-2014 at 02:50

what about this method

start from lysine -can be obtained at nutrient stores

http://www.amazon.com/L-Lysine-1000g-Powder-Pharmaceutical-Q...

then do strecker degradation with hypochlorite
http://en.wikipedia.org/wiki/Strecker_degradation

you will get 5-aminopentanal (i have read in the acetaldehyde synthesis thread in organic chemistry section that you might get primary nitriles but that's ok as the nitriles will get hydrolysed to the acid that i am eventually going to make)

treat this with HNO₂ (NaNO₂ +HCl) ,you could get nitrite from butcher salts as chemosynthesis said

this will convert the terminal amine to alcohol
so you have 5-hydroxypentanal
now oxidise this with KMnO₄(alkaline not acidic) to get pentan-1,4 dioc acid or glutaric acid
http://en.wikipedia.org/wiki/Glutaric_acid

esterify with ethanol to get diester
now is the hard part
treat this with grignard(methyl magnesium iodide) to convert it to tertiary alcohol
http://www.sciencemadness.org/talk/viewthread.php?tid=12475

i know that Mg is not OTC ,so you can use methyl lithium instead ,but methyl lithium is pyrophoric

now ,get completely anhydrous ethanol(you can get that by distilling the 95% alcohol with CaCl₂ or MgCl₂) and pass ammonia through that(you would have to dry the ammonia gas first by passing it through a tube packed with NaOH pellets)

then react this ethanolic solution with the diol to get cyclic amine
as the absolute alcohol acts as a dehydrating agent
http://www.inkling.com/read/suvarna-bancrofts-theory-practic...

then you can oxidise the cyclic amine to get TEMPO

i have a little doubt in the last step of the dehydration
as sulphuric acid cannot be used as that will react with the ammonia
so are there other dehydrating agents that are basic
also would refluxing the diol with ammonia in the presence of oven heated silica gel(found in shoe boxes,electronics) help

[Edited on 22-11-2014 by CuReUS]

CuReUS - 23-11-2014 at 09:23

i made a slight error while naming a compound in my previous post.
when you oxidize 5-hydroxypentanal with KMnO₄ ,you get pentane-1,5 dioc acid ,not pentane 1,4 dioc acid as I said .

now the last step is a bit fishy and most probably it wont work,as the alcohol acts as a dehydrating agent for free water or water of crystallization ,it cant dehydrate alcohols to give ethers or things like that ,which sulphuric acid and other chemicals can do

the logic that I had in mind was that in the last step when the diol is dehydrated ,if it is done only in the presence of a dehydrating agent,you would get a cyclic ether
but if ammonia was there,then being a better nucleophile .it would give its lone pair to the carbocation formed
but sadly the formation of cyclic ethers is an S_N2 reaction
http://en.wikipedia.org/wiki/Diol#General_diols

so the logic wont work anyways :mad:

so then you would have to do three more steps
convert the diol to dichloro (since it is tertiary ,i think dilute HCl will be enough,also no rearrangement as tertiary is the most stable)

dehydrohalogenate using alcoholic KOH to form alkene
now add ammonia to it with a liitle modification

if you add ammonia to phorone ,it gives TEMP due to conjugate addition reaction
http://en.wikipedia.org/wiki/2,2,6,6-Tetramethylpiperidine

since the alkene has no carbonyl group to activate it.,we cannot add ammonia directly
so we put the alkene in a bomb or a pipe or even a pressure cooker with lot of ammonia and heat it
the pressure helps to add the ammonia
http://books.google.co.in/books?id=NJJ7AgAAQBAJ&pg=PA121...
and you get TEMP which can finally be oxidized to TEMPO

i remember reading once that you could swap the oxygen of a cyclic ether with nitrogen to get a cyclic amine,but i cant remember the name of that reaction

has anyone heard of or read of such a reaction
if that reaction was possible ,then the diol would first be converted to cyclic ether and then the O would be swapped for N ,to get TEMP

i saw a video on using methyl lithium
http://www.youtube.com/watch?v=K5NuqpdYDhE

do we really need that syringe pump
seems to high tech

Jylliana - 23-11-2014 at 09:38

All I want to say here is that I love TEMPO because it looks like a tiny spaceship :cool:

What has been seen, cannot be unseen

Metacelsus - 23-11-2014 at 09:46

My recrystallization of the crude triacetoneamine hydrochloride from isopropanol is almost done.

Here's what I've done so far:
1: Added ammonia gas to acetone, methanol, and ammonium chloride,
2: Reacted it at 50 C overnight,
3: Evaporated off the excess solvent under vacuum to leave a red sludgy residue,
4: Added 12 M hydrochloric acid until the pH was 4,
5: Distilled off the water and excess acid under vacuum,
6: Dissolved the residue in boiling isopropanol,
7: Filtered out insoluble impurities (like ammonium chloride),
8: Cooled the solution in an ice bath* (I'm doing this now, and crystals are forming).

Pictures will come soon, and I'll also verify that I have an amine salt by adding crystals to concentrated NaOH.

*Also known as a snowbank.

[Edited on 23-11-2014 by Cheddite Cheese]

mr.crow - 23-11-2014 at 10:56

TEMPO sounds really interesting

Here is an old thread with lots of nice pictures for reference

Metacelsus - 23-11-2014 at 11:21

Yes, I've read that thread and found it very helpful.

Initial yield of triacetoneamine hydrochloride crystals: 19.87 g (103.7 mmol). I started with 175 mL acetone, using the method Klute did in the old thread, so the yield seems reasonable. He got 10.7 g from 100 mL acetone. Klute's description of the residue after solvent removal being a "thick black/red syrup" is quite apt.
I will recrystallize the product a second time from isopropanol, because it doesn't look pure. It's hard to see in the picture, but there are small, colorless crystals mixed with brown powder. I also added some of the product to sodium hydroxide solution, and observed an upper liquid layer form, with a characteristic amine smell.

Photo on 11-23-14 at 12.27 PM.jpg - 205kB

Photo on 11-23-14 at 12.40 PM #2.jpg - 214kB

[Edited on 23-11-2014 by Cheddite Cheese]

blogfast25 - 23-11-2014 at 11:38

Geez, your shed looks a bit like mine. But you rack seems straighter...

Very nice progress, indeed.

Metacelsus - 23-11-2014 at 13:40

The second recrystallization was successful. I now have nice, colorless crystals (mass 12.61 g). I don't mind the loss much, as the purity is greatly improved.

Photo on 11-23-14 at 3.39 PM.jpg - 228kB

[Edited on 23-11-2014 by Cheddite Cheese]

Etaoin Shrdlu - 23-11-2014 at 14:17

Oh wow, that second recrystallization looks very nice.

aga - 23-11-2014 at 14:41

V. Nice !

Before anyone says anything about Cleanliness, a tidy shed, and a clean hotplate is not a sign of an organised mind : it is just proof of inactivity.

That shed and hotplate see Action a lot !

Edit:

The lab coat is too clean.
It looks brand new.
Borrowed a Prop for the photo shoot ?

[Edited on 23-11-2014 by aga]

Metacelsus - 23-11-2014 at 14:47

No, the stains are just out of the field of view.

CuReUS - 24-11-2014 at 09:20

Quote: Originally posted by Jylliana

All I want to say here is that I love TEMPO because it looks like a tiny spaceship :cool:

i like the way you relate the structure of the compound with an object as it makes it more easy to remember and reproduce later

but TEMPO is a toy compared to Vitamin B12
that's one spaceship even Jedi would envy

http://books.google.co.in/books?id=JX7AAgAAQBAJ&pg=PA848...

back to my cyclic ether idea
the S_n2 reaction is influenced by strength and concentration of the nucleophile
so my logic of the N of ammonia entering the ring when the first O is protonated ,as N is a better nucloephile than O ,might actually work

now i just have to find the right name reaction to prove my point

[Edited on 25-11-2014 by CuReUS]

Etaoin Shrdlu - 9-1-2015 at 17:59

Just making a mention that this is still open.

Metacelsus - 18-1-2015 at 15:52

The Clemmensen reduction is underway (refluxing as I post).

5 g oxo-amine hydrochloride (26 mmol) dissolved in 25 mL warm methanol
17 g Zn powder (260 mmol) (5x excess)
0.8 g Hg(NO3)2 (freshly prepared, and not isolated)
45 mL 12 M HCl (520 mmol)

Everything is going well so far, and I'll post pictures soon-ish.

The reduction is done (all the Zn is dissolved, at least). It took 3 hours. I'll do the workup tomorrow morning.

One question: I want to analyze the reaction products by TLC on silica gel plates. I'll probably analyze the freebases instead of the salts, since I think that they will separate better. I doubt the compounds will fluoresce under UV light, so my question is: how can I visualize the results?

[Edited on 19-1-2015 by Cheddite Cheese]

Chemosynthesis - 19-1-2015 at 10:16

It's been awhile since I've had to stain a TLC plate, but there are quite a few different ones you can choose from that you probably aren't necessarily familiar with. Iodine, cerium sulfate, and vanillin may be among the most readily accessible general stains in keeping with the OTC nature of the thread. Here are quite a few with preparations.

http://www.chemistry.mcmaster.ca/adronov/resources/Stains_fo...

Clemmensen Reduction Pictures (1)

Metacelsus - 19-1-2015 at 13:29

The reagents

Mercury

Zinc

Substrate

Mercury in a test tube

Dissolving mercury in nitric acid

Refluxing the reaction mixture

Three hours later: decanting the reaction mixture from the residue (mostly Hg)

[Edited on 19-1-2015 by Cheddite Cheese]

Clemmensen Reduction Pictures (2)

Metacelsus - 19-1-2015 at 13:31

Sodium hydroxide

Extraction with toluene after basifcation (ppt. is Zn(OH)₂)

Extraction with hydrochloric acid

After evaporation of acid

Recrystallization

Collection of crystals by vacuum filtration

Close-up of crystals

Mass of crystals is 1.194 g

As of now, I have not conclusively determined that the oxo group is gone. I will work on this over the next week (when I have time, at least).

About staining: I doubt the compound will react with iodine, and I don't have most of the other stains. I could try potassium permanganate, or possibly dinitrophenylhydrazine (which I don't have, but could prepare, although I don't really want to).

[Edited on 19-1-2015 by Cheddite Cheese]

TLC results

Metacelsus - 22-3-2015 at 09:12

I finally got around to doing TLC. Compound before reduction is on the right, compound after reduction is on the left. Both compounds were spotted as a solution of the hydrochloride. I used acetone to elute the plate, and alkaline permanganate as a stain. To get the stain to develop, I heated the TLC plate on the hot plate at the lowest setting. The time between when the spots appeared and when all the permanganate had decomposed was only a few minutes, but the spots were clearly visible as tan on a pink background, and I circled them lightly in pencil (sorry for the bad lighting in the photo).

Retention factor for compound before reduction: 5.5 cm / 6.9 cm = 0.80

Retention factor for compound after reduction: 6.6 cm / 6.9 cm = 0.96

Photo on 3-22-15 at 11.59 AM.jpg - 163kB

I wish I could have used a solvent less polar than acetone, but acetone was the least polar solvent I have that doesn't react easily with permanganate. (I have toluene, but that would react.) Something like a mixture of hexanes and ethyl acetate (which I used in my organic chemistry lab class) would be ideal. If these results don't meet the challenge expectations, I could try making some diethyl ether and using that. However, I think that these results show clearly enough that the two compounds are pure, that they are different, and that the compound after reduction is less polar than the compound before reduction.

Next step: oxidation to TEMPO. I plan to use Klute's method, with hydrogen peroxide. I'll start by concentrating some OTC 3% solution by gentle evaporation.

[Edited on 22-3-2015 by Cheddite Cheese]

Etaoin Shrdlu - 22-3-2015 at 11:25

Sorry I missed the January updates somehow. That looks fantastic.

byko3y - 22-3-2015 at 19:16

Cheddite Cheese, you would really wanted to read this doc before attempting to do clemmensen on the mannich base (which is a OC-C-C-N group). See attachment below.
Probably you've got an unsaturated compound. You didn't do the melting point check on the resulting amine, it would probably show if you've got the right substance.
Also there's a successful synthesis of 4-oxo-xxxpyperidine and it's subsequent oxidation on this forum http://www.sciencemadness.org/talk/viewthread.php?tid=3960&a...

Attachment: Clemmensen reduction of mannich bases. Potential ganglionic and nicotinic agents.pdf (329kB)
This file has been downloaded 535 times

Chemosynthesis - 23-3-2015 at 00:00

Very exciting; we have updates and dissent! Welcome aboard, byko3y.

CuReUS - 23-3-2015 at 01:44

Quote: Originally posted by byko3y

Cheddite Cheese, you would really wanted to read this doc before attempting to do clemmensen on the mannich base (which is a OC-C-C-N group).
Probably you've got an unsaturated compound.

I was expecting something to go wrong with the clemmenson,maybe a crazy polymerisation to yield a tarry goo or some ring contraction.But the confidence with which cheddite extracted his product and purified it made me doubt myself,whether I was being too pessimistic
but mannich bases,decompose at temp above 120'C and I don't think the reflux temp went that high,did it ?

DJF90 - 23-3-2015 at 05:37

I finally got around to doing TLC. Compound before reduction is on the right, compound after reduction is on the left. Both compounds were spotted as a solution of the hydrochloride. I used acetone to elute the plate, and alkaline permanganate as a stain. To get the stain to develop, I heated the TLC plate on the hot plate at the lowest setting. The time between when the spots appeared and when all the permanganate had decomposed was only a few minutes, but the spots were clearly visible as tan on a pink background, and I circled them lightly in pencil (sorry for the bad lighting in the photo).

When using amine salts for TLC analysis, you should also have ammonia or triethylamine present in your solvent system in order to liberate the free base. The quick discolouration of the background sounds like you've not thoroughly dried your plate before staining (and the residual acetone is reducing the permanganate) or your temperature is too high. I use a digital heat gun and typically with permanganate you're talking 30 seconds to 1 minute at 80-150 *C (depending on how easily oxidised the compounds are).

Any solvent can be used for developing TLC plates, regardless of which stain you intend to use. The key thing to ensure is that the plate is thoroughly dry before staining. This can be done by leaving it to evaporate for 5 mins, gently heating with a heat gun (ca 50 to 60 *C), or if your compounds may be heat labile, under reduced pressure (vacuum dessicator works well for this).

However, I think that these results show clearly enough that the two compounds are pure, that they are different, and that the compound after reduction is less polar than the compound before reduction.

Not quite. Impurities can be pretty good at hiding, and I've seen such instances first hand multiple times (I'm a chemist by profession...). I have a couple of guidelines that might help you out a bit though:

a) For a given solvent system, try to get your analyte close to the middle of the plate (by adjusting the ratios of the solvents). Ideally, we're talking Rf = 0.3 to 0.7. The reason for this is that at low Rfs its difficult to clearly see separation, and at high Rfs several components can quite easily "bunch together"

b) Visualise your plate by several methods. Unfortunately its not often possible to see everything using one approach. You should definitely have a look under both short- (254 nm) and long- (365 nm) wave UV before using any stain.

c) Evaluate your compound using several different solvent mixtures. I've had cases recently where two compounds almost co-elute in several different solvent systems (they fluoresced different colours under long-wave UV), but was fortunate enough to find a system that did provide separation. You have several options depending on the polarity of your analytes; you'll get a feel for whats "about right" as you gain experience.

Please bear in mind that this advice is general and intended to be helpful.

Quote: Originally posted by byko3y

Cheddite Cheese, you would really wanted to read this doc before attempting to do clemmensen on the mannich

base (which is a OC-C-C-N group). See attachment below.
Probably you've got an unsaturated compound. You didn't do the melting point check on the resulting amine, it would probably show if you've got the right substance. Also there's a successful synthesis of 4-oxo-xxxpyperidine and it's subsequent oxidation on this forum http://www.sciencemadness.org/talk/viewthread.php?tid=3960&a...

I've glanced over the attached paper and found that all the examples are benzylic ketones; it may be that the mode of reaction is specific to that structural motif. Whilst it is worth bearing in mind, I don't think we'll see any unsaturated species using triacetoneamine as substrate. I do however strongly second your suggestion to run a melting point, especially if theres a literature value for triacetoneamine hydrochloride.

[Edited on 23-3-2015 by DJF90]

Metacelsus - 23-3-2015 at 06:27

I feel so stupid now for not realizing that I could use a different solvent, and it would be fine because it would evaporate. I did, however, let all the acetone evaporate before staining. The quick staining and decomposition is probably a result of the level of heat I used.

I'll do the TLC again with toluene and triethylamine. Permangante and iodine are the only stains I have right now. Iodine wouldn't react very well with the compounds I think I have, but if an alkene was present, it would show it.

I don't have UV lamps. (I did have one about a year ago, but the ballast quit working.) I can do a melting point check, but I don't have a dedicated melting point apparatus. I'll have to use an oil bath.

Etaoin Shrdlu - 23-3-2015 at 07:26

Very exciting; we have updates and dissent! Welcome aboard, byko3y.

Very much welcome, that was an excellent first post.

That paper is interesting, not something I'd heard about before. For the statement that Clemmensen reduction of Mannich bases tends to produce alkene byproducts, they reference Reduction: Techniques and Applications in Organic Synthesis, by Robert L. Augustine, pp. 186-194. I'll ask in References as well, but has anyone got a copy of this and can scan or summarize it? I would be interested to know if it discusses substrates where the ketone is not benzylic. Supposedly there's one on Amazon for $20 but I'm a bit nervous of buying it when the others are all around $215.

[Edited on 3-23-2015 by Etaoin Shrdlu]

DJF90 - 23-3-2015 at 08:14

I'll do the TLC again with toluene and triethylamine.

I don't think that toluene itself will move the analytes much - use it as the non-polar component of a mixture (perhaps with EtOAc or acetone - try 1:1 first for an idea of which direction to move in). Also, go easy on the triethylamine - 0.1%v/v ought to do it. You'll have to heat the plate (gently) after elution to get it to bugger off though.

Permangante and iodine are the only stains I have right now. Iodine wouldn't react very well with the compounds I think I have, but if an alkene was present, it would show it.

Both are good general stains. Iodine will typically stain most things by dissolution in the organic substance (giving dark brown spots on a light brown background), whereas reaction with the analyte will give white spots.

I don't have UV lamps. (I did have one about a year ago, but the ballast quit working.) I can do a melting point check, but I don't have a dedicated melting point apparatus. I'll have to use an oil bath.

They aren't too expensive and I've posted before on this...

Quote: Originally posted by DJF90

For those in the UK, you can buy a counterfeit money detector from Maplin (http://www.maplin.co.uk/p/professional-3-tube-money-detector...). This is an updated model to the one I purchased a couple of years ago, which came with a blacklight bulb which is typical for long wave detection (365 nm ish...). This new model claims to have two UV bulbs and a white bulb also, so perhaps it already has detection at 254nm also. Otherwise, I purchased a 4W germicidal bulb on ebay that will fitted my lamp, allowing detection for plates using a 254nm fluorescent material.

TLC (round 2)

Metacelsus - 23-3-2015 at 12:14

Eluent this time was 40% acetone, 59% toluene, 1% triethylamine. I used minimal heat when developing, so I managed to get a picture in which the stain had not faded (because of this, there are a few drops of stain solution left on the plate, and although they obscure the bottom part of the plate in the picture, there are no spots in that area.)

Rf for compound with suspected ketone group: 3.2/7.0 = 0.46
Rf for compound after reduction: 4.8/7.0 = 0.69

[Edited on 23-3-2015 by Cheddite Cheese]

Chemosynthesis - 23-3-2015 at 13:22

Good catch, DFJ90, as expected from the consistent high quality of your posts. Cheddite, as noted, you had it right with the free bases in your earlier post. Ammonia is good (gaseous or aqueous choice can theoretically change solvent characteristics), though I have seen hydroxides used before. Drying is important with the triethylamine you used as well, since that can sometimes show up with stains. When not used in the actual solvent system, I have seen people go nuts over this mysterious impurity (starting material didn't require it in that case). You can get doubling or streaking of amine spots otherwise due to protonation equilibrium. In the same manner, a carboxylic acid may require addition of a stronger acid to shift towards the protonated form.

I haven't read the paper yet, but I second/third a melting point. If it's broad and/or depressed, you should try a 2D TLC. They are very useful. Very rare to just pick one solvent system for TLC and call it a day. And I actually prefer iodine for staining, often. One useful aspect is that it can be very labile and volatile, and so with time, a second stain can be performed if your organics are stable. Sometimes doing a second stain, using a UV lamp, or running a 2D TLC will show a surprise before you get a MP, which can be more of an issue when checking column fractions.

Metacelsus - 23-3-2015 at 15:35

Sigma-Aldrich (http://www.sigmaaldrich.com/catalog/product/sigma/t4694) lists the melting point of 2,2,6,6-tetramethylpiperidine hydrochloride as 299-301 C. I have currently no way of measuring temperatures that high (the highest I can measure is 250 C), so a melting point determination is out of the question. I might be able to prepare a different salt, and find a reference for that.

I also found Sigma's listing for the 4-oxo-2,2,6,6-tetramethylpiperidine hydrochloride (http://www.sigmaaldrich.com/catalog/product/fluka/87910), which cites a melting point of 198 C with decomposition. I'm not sure how useful that is.

I really wish I could just take an NMR spectrum.

[Edited on 23-3-2015 by Cheddite Cheese]

byko3y - 23-3-2015 at 16:59

2,2,6,6-tetramethylpiperidine freebase boiling point is 152 C. Actually, in the first post I wanted to say "boiling point" instead of melting.

DJF90 - 24-3-2015 at 04:45

Eluent this time was 40% acetone, 59% toluene, 1% triethylamine. I used minimal heat when developing, so I managed to get a picture in which the stain had not faded (because of this, there are a few drops of stain solution left on the plate, and although they obscure the bottom part of the plate in the picture, there are no spots in that area.)

Rf for compound with suspected ketone group: 3.2/7.0 = 0.46
Rf for compound after reduction: 4.8/7.0 = 0.69

Much better, well done. It looks like you're sat on the floor to take that picture?

Good catch, DFJ90, as expected from the consistent high quality of your posts.

Cheers. I've considered writing a blog or a web page or something but just don't have the time.